U.S. patent number 6,528,693 [Application Number 09/806,980] was granted by the patent office on 2003-03-04 for preparation of cyclopropylethyne and intermediates for preparation of cyclopropylethyne.
This patent grant is currently assigned to Great Lakes (UK) Limited. Invention is credited to Peter John Cremins, Robert Gandy, Allan Williams Timms.
United States Patent |
6,528,693 |
Gandy , et al. |
March 4, 2003 |
Preparation of cyclopropylethyne and intermediates for preparation
of cyclopropylethyne
Abstract
1-chloropropylethyne is prepared by dehydrochlorination with a
base of 1-chloro-1-cyclopropylethene, which is itself prepared by
treating 1-cyclopropylethanone with dichlorotriarylphosphorane or
dichlorotrialkylphosphorane in the presence of a base.
Inventors: |
Gandy; Robert (Liverpool,
GB), Cremins; Peter John (Manchester, GB),
Timms; Allan Williams (Ellesmere Port, GB) |
Assignee: |
Great Lakes (UK) Limited
(Cheshire, GB)
|
Family
ID: |
10826913 |
Appl.
No.: |
09/806,980 |
Filed: |
April 5, 2001 |
PCT
Filed: |
October 12, 1998 |
PCT No.: |
PCT/GB98/03043 |
PCT
Pub. No.: |
WO00/21912 |
PCT
Pub. Date: |
April 20, 2000 |
Current U.S.
Class: |
570/217; 585/312;
585/317; 585/359 |
Current CPC
Class: |
C07C
1/30 (20130101); C07C 13/04 (20130101); C07C
17/00 (20130101); C07F 9/535 (20130101); C07C
1/30 (20130101); C07C 13/04 (20130101); C07C
17/00 (20130101); C07C 22/00 (20130101); C07C
2601/02 (20170501) |
Current International
Class: |
C07C
1/00 (20060101); C07C 13/04 (20060101); C07C
13/00 (20060101); C07C 1/30 (20060101); C07C
17/00 (20060101); C07F 9/00 (20060101); C07F
9/535 (20060101); C07C 017/02 (); C07C
002/00 () |
Field of
Search: |
;570/217
;585/317,312,359 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
2 329 384 |
|
Mar 1999 |
|
GB |
|
WO9840333 |
|
Sep 1998 |
|
WO |
|
WO 98/40333 |
|
Sep 1998 |
|
WO |
|
Other References
Chemical Abstracts 87:200900 (1977), abstracting Soviet Union
Patent 555079, issued Apr. 25, 1977. .
Chemical Abstracts 88:89193 (1978), abstracting Soviet Union Patent
572445, issued Sep. 15, 1977. .
Chemical Abstracts 88:89194 (1978), abstracting Soviet Union Patent
578293, issued Oct. 30, 1977..
|
Primary Examiner: Siegel; Alan
Attorney, Agent or Firm: Drinker Biddle & Reath LLP
Parent Case Text
This application is a 371 of PCT/GB98/03043 filed Oct. 12, 1998.
Claims
What is claimed is:
1. A process for preparation of 1-chloro-1-cyclopropylethene
comprising treating 1-cyclopropylethanone with
dichlorotriarylphosphorane or dichlorotrialkylphosphorane in the
presence of a base comprising a tertiary amine in an inert solvent,
wherein the dichlorotriarylphosphorane is formed in situ by
reaction of a triarylphosphine or triarylphosphine oxide with
phosgene, and the dichlorotrialkylphosphorane is formed in situ by
reaction of a trialkylphosphine or trialkylphosphine oxide with
phosgene.
2. A process as claimed in claim 1, wherein the base is pyridine or
quinoline.
3. A process as claimed in claim 1, wherein the solvent is an
aromatic solvent.
4. A process as claimed in claim 3, wherein the solvent is
1,2-dichlorobenzene.
5. A process as claimed in claim 1, wherein the reaction is carried
out between ambient temperature and 100.degree. C.
6. A process as claimed in claim 5, wherein the reaction
temperature is 70.degree. C. to 80.degree. C.
7. A process as claimed in claim 1, wherein the
dichlorotriaryphosphorane is dichlorotriphenylphosphorane.
8. A process as claimed in claim 1 wherein 1-100 mol % of
tri-substituted phosphine or its oxide is used.
9. A process as claimed in claim 8, wherein 1-10 mol % of
tri-substituted phosphine or its oxide is used.
10. A process as claimed in claim 1 further comprising the step of
dehydrochlorinating the 1-chloro-1-cyclopropylethene with a strong
base in an inert solvent to form cyclopropylethyne.
11. A process for preparing cyclopropylethyne comprising the steps
of preparing 1-chloro-1-cyclopropylethene by chlorinating
dichlorotriarylphosphorane or dichlorotrialkylphosphorane in the
presence of a base comprising a tertiary amine in an inert solvent
and dehydrochlorinating the 1-chloro-1-cyclopropylethene with a
strong base in an inert solvent, wherein the
dichlorotriarylphosphorane is formed in situ by reaction of a
triarylphosphine or triarylphosphine oxide with phosgene, and the
dichlorotrialkylphosphorane is formed in situ by reaction of a
trialkylphosphine or trialkylphosphine oxide with phosgene.
12. A process as claimed in claim 11, where the base in the
chlorination stage is pyridine or quinoline.
13. A process as claimed in claim 11, wherein the solvent in the
chlorination stage is an aromatic solvent.
14. A process as claimed in claim 13, wherein the solvent is
1,2-dichlorobenzene.
15. A process as claimed in claim 11, wherein the temperature of
the chlorination stage is in the range of ambient temperature to
100.degree. C.
16. A process as claimed in claim 15, wherein the reaction
temperature is 70.degree. C. to 80.degree. C.
17. A process as claimed in claim 11, wherein the
dichlorotriarylphosphorane is dichlorotriphenylphosphorane.
18. A process as claimed in claim 11 wherein 1-100 mol % of
tri-substituted phosphine or its oxide is used.
19. A process as claimed in claim 18, wherein 1-10 mol % of
tri-substituted phospine or its oxide is used.
20. A process as claimed in claim 11, wherein the base in the
dehydrochlorination stage is an alkali metal or alkaline earth
hydroxide.
21. A process as claimed in claim 11, wherein the base in the
dehydrochlorination stage is an alkali metal salt of an
alcohol.
22. A process as claimed in claim 20, wherein the base in the
dehydrochlorination stage is sodium hydroxide.
23. A process as claimed in claim 21, wherein the base in the
dehydrochlorination stage is sodium .sup.t- butoxide.
24. A process as claimed in claim 11, wherein the
dehydrochlorination stage is carried out in a dipolar protic or
aprotic solvent.
25. A process as claimed in claim 24, wherein the solvent is
dimethyl sulphoxide.
26. A process as claimed in claim 24, wherein the solvent is
ethylene glycol.
27. A process as claimed in claim 11, wherein the temperature of
the dehydrochlorination stage is in the range of ambient
temperature to 100.degree. C.
28. A process as claimed in claim 27, wherein the temperature of
the dehydrochlorination stage is in the range 55.degree. C. to
65.degree. C.
Description
DESCRIPTION
This invention concerns a process for preparing cyclopropylethyne
as well as a process for preparing intermediates for making
cyclopropylethyne.
Cyclopropylethyne is used, for example, as an intermediate in the
synthesis of the important HIV reverse transcriptase inhibitor of
the following structure: ##STR1##
There are two main syntheses for cyclopropylethyne already
disclosed in the literature. These are: 1. Chlorination of
cyclopropyl methyl ketone with phosphorus pentachloride to give
1,1-dichloro-1-cyclopropylethane followed by dehydrochlorination
with a strong base ##STR2## 2. Reaction of 5-chloro-1-pentyne with
2 equivalents of butyl lithium to effect cyclisation. ##STR3##
Whilst these methods work well on a laboratory scale, manufacture
on a production scale is difficult. The intermediate,
1,1-dichloro-1-cyclopropylethane produced in the first literature
route is a very labile molecule and is thermally and hydrolytically
unstable. For example, whilst chlorination of cyclopropyl methyl
ketone with phosphorus pentachloride proceeds quite well even on a
large scale, the isolation of the 1,1-dichloro-1-cyclopropylethane
from the reaction mixture (which necessarily contains phosphorus
oxychloride) can lead to extensive decomposition of the product.
The phosphorus oxychloride may be removed by decomposition with
water. Such a process is very exothermic and unless the reaction
mixture is kept cool the product is decomposed by both aqueous
acids and alkalis. The cooling requirements on a plant scale would
be enormous. This leads to a very high capital investment in plant.
If the feed time is extended to overcome the deficiencies in the
cooling systems, decomposition also occurs and leads to very low
yields of the target compound.
It is also possible to remove the phosphorus oxychloride by
fractional distillation. However, in a conventional pot still,
extensive decomposition due to ring opening can occur resulting in
low yields.
Once the required 1,1-dichloro-1-cyclopropylethane has been
obtained in a pure form, dehydrochlorination to give the required
compound can also lead to problems. As stated above, the compound
is both thermally unstable and also unstable to alkalis. Thus to
effect dehyrochlorination, a hindered base in a dipolar aprotic
solvent is required so that elimination rather than substitution is
the major synthetic pathway. Because of the stoichiometry of the
process at least two equivalents of expensive base are required.
This seriously increases the cost of manufacture.
The method of manufacture where 5-chloro-1-pentyne is ring closed
by means of at least 2 equivalents of n-butyl lithium also works
quite well in the laboratory. However, the cost of n-butyl lithium
makes manufacture by this route an expensive option. Furthermore,
specialised plant is required to handle the pyrophoric concentrated
solutions that an efficient synthesis dictates.
WO98/40333A (BASF Aktiengesellschaft) discloses a process for
halogenating cyclopropylmethyl ketone with at least one dihalogen
triorganophosphorane as well as a process for converting the
halogenated cyclopropyl methyl ketone into
cyclopropylacetylene.
A first object of this invention is to provide a process for
preparing an intermediate for preparation of cyclopropylethyne,
which is both thermally and hydrolytically stable and does not
involve use of expensive pyrophoric reagents.
A second object of this invention is to provide an improved process
for preparing cyclopropylethyne.
It has been surprisingly found that a suitable intermediate for use
in preparing cyclopropylethyne is 1-chloro-1-cyclopropylethene.
According to a first aspect of this invention there is provided a
process for preparing 1-chloro-1-cyclopropylethene comprising
treating 1-cyclopropylethanone with dichlorotriaryl phosphorane or
dichlorotriakyl phosphorane in the presence of a base in an inert
solvent characterised in that the base is a tertiary amine.
According to a second aspect of this invention there is provided a
process for preparing cyclopropylethyne comprising the steps of
preparing 1-chloro-1-cyclopropylethene by chlorinating
1-cyclopropylethanone with dichlorotriarylphosphorane or
dichlorotriakylphosphorane in the presence of a base in an inert
solvent and dehydrochlorinating the 1-chloro-1-cyclopropylethene
with a strong base in an inert solvent, characterised in that the
base in the chlorination stage is a tertiary amine.
The 1-chloro-1-cyclopropylethene used in the process of the second
aspect of the invention may be that prepared by the process of the
first aspect of the invention.
A benefit of using 1-chloro-1-cyclopropylethene is that, in
principle, only one equivalent of strong base is required to bring
about the dehydrochlorination. Furthermore, this base does not need
to be an expensive alkali metal salt of a hindered tertiary
alcohol. Simple hydroxides of alkali metals will suffice to bring
about the transformation. The literature indicates that this
intermediate may be prepared in reasonable yield by the
mono-dehydrochlorination of 1,1-dichloro-1-cyclopropylethane; an
intermediate which has already been stated to be difficult to
manufacture on a large scale. A better synthesis of
1-chloro-1-cyclopropylethene was therefore sought. ##STR4##
It is known that acetyl ketones will react with
dichlorotriphenylphosphorane to afford the corresponding gem
dichlorides. (U.S. Pat. No. 3,715,407). The reaction in the case of
cyclopropyl methyl ketone has the complication that the
cyclopropane ring is ruptured during the course of the reaction
with the formation of compounds which were identified as
dichloropentenes. It was considered that these by-products were
formed by adventitious hydrogen chloride in the reaction mixture
and that the inclusion of an organic base would prevent this side
reaction occuring. When this experiment was carried out, the amount
of ring opened dichloropentenes was greatly reduced from an
experiment which did not contain base. We were surprised to find
that only minor amounts of 1,1-dichloro-1-cyclopropylethane were
formed but that 1-chloro-1-cyclopropylethene was formed in good
yield. Furthermore, the amount of ring opened dichloropentenes were
greatly reduced from an experiment which did not contain base. A
convenient synthesis of the desired intermediate was thus opened to
us. ##STR5##
wherein R is an aryl group or an alkyl group.
The dichlorothiarysphohranes or the dichlorotrialkylphosphoranes
may be prepared by reaction of the appropriate triarylphosphine or
triarylphosphine oxide or trialkylphosphine or trialkylphosphine
oxide with a chlorinating agent such as chlorine or phosgene. The
chlorination stage may be carried out catalytically in situ
particularly if phosgene is used. 1-100 mol % of trisubstituted
phosphine or its oxide may be used. Less than 25 mol % of
triarylphosphine or its oxide or trialkylphosphine or its oxide may
be sufficient to bring about the transformation with 1-10 mol %,
more preferably about 6 mol %, being close to the optimum in terms
of yield and reaction velocity.
The organic base that is required for good reaction can be any base
which does not react with phosgene or dichlorotriarylphosphorane or
dichlorotrialkylphosphorane. In practice this means that tertiary
amines are probably most suitable as the organic base. Pyridine and
quinoline are particularly suitable since they appear to be inert
to the phosgenation reaction conditions. Other tertiary amines such
as triethylamine which may be used are less suitable since they can
preferentially react with phosgene under the reaction conditions to
give carcinogenic carbamoyl chlorides such as diethyl carbamoyl
chloride. The production of even minor amounts of such carcinogens
precludes the use of such tertiary amines in large scale
manufacture.
As already described the thermal and hydrolytic stability of
1-chloro-1-cyclopropylethene is much greater than
1,1-dichloro-1-cyclopropylethane. This means that the work-up of
the product is much simpler. The product may be distilled directly
from the reaction mixture or quenched on to aqueous alkali and then
phase separated from the aqueous layer and the organic phase
fractionated. Due to formation of molar quantities of amine
hydrochloride, it is necessary to use a solvent to provide mobility
for the reaction. Almost any solvent which does not react under the
reaction conditions may be used but it is most convenient to use
one of sufficiently different boiling point which does not
interfere with the distillation of the product,
1-chloro-1-cyclopropylethene, from the reaction mixture. Aromatic
solvents, especially high boiling aromatic solvents are
particularly useful since the reactants are soluble in these
solvents and the distillation of the product from them is easy.
1,2-Dichlorobenzene is particularly usefull as a solvent.
The reaction is conveniently carried out in a temperature range of
ambient, say, around 20.degree. C., to about 100.degree. C. At
lower temperatures the reaction rate is such that the synthesis
cannot be carried out in a reasonable time. At higher temperatures
by-products begin to be formed with the concomitant reduction in
yield. The optimum temperature in terms of reaction rate and
specificity appears to be between 40.degree. C. and 90.degree. C.,
more preferably 70.degree. C. to 80.degree. C.
Dehydrochlorination of 1-chloro-1-cyclopropylethene can be effected
with strong bases in a suitable solvent, for example any alcohol.
Such strong bases are the alkali metal salts of hindered tertiary
alcohols, alkali or alkaline earth hydroxides or the "super-bases".
Examples of these bases are sodium or potassium .sup.t- butoxide,
sodium or potassium hydroxide or
2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine. Particularly
useful are the alkali metal hydroxides with sodium hydroxide being
very advantageous.
The solvent for the dehydrochlorination can be almost any solvent
which does not react under the basic, hydrolytic conditions.
Dipolar protic or aprotic solvents such as dimethyl sulphoxide are
useful as solvent as are high boiling alcohols such as ethylene
glycol. The temperature is not critical to the outcome of the
reaction. The temperature is preferably in the range of ambient
temperature to 100.degree. C., preferably 55.degree. C. to
65.degree. C. Temperatures of about 60.degree. C. appear to be
satisfactory in terms of reaction rate. At the end of the reaction
time, the product, cyclopropylacetylene, is isolated by simple
ionation from the reaction mixture.
This invention will now be further described by means of the
following Examples
EXAMPLE 1
Preparation of 1-chloro-1-cyclopropylethene
Gaseous phosgene (480 g, 4.85 mol) was passed into a sired solution
of cyclopropyl methyl ketone (336 g, 4.0 mol), triphenylphosphine
oxide (68 g, 0.25 mol) and quinoline (774 g, 6.0 mol) in
1,2-dichlorobenzene (280 cm.sup.3) over a period of 6 to 7 hours at
70.degree. C. to 80.degree. C. An exothermic reaction occurred,
carbon dioxide gas was evolved, and the reaction mixture gradually
darkened to form a very dark mobile slurry. On completion of
phosgene addition, the reaction mixture was warmed to 90.degree. C.
and then stirred at 90.degree. C. to 100.degree. C. for a further 5
hours to complete the reaction. The mixture was then cooled to
75.degree. C. and the product, 1-chloro-1-cyclopropylethene removed
by flash distillation by applying a vacuum of about 80 mm Hg.
The distillate, containing small amounts of dichloropentenes,
1,2-dichlorobenzene and quinoline was fractionated through a short
fractionating column. 1-Chloro-1-cyclopropylethene (223 g, 54.7%)
was obtained in >97% assay of bp 95.degree. C. to 99.degree.
C.
EXAMPLE 2
Preparation of cyclopropylethyne
1-chloro-1-cyclopropylethene prepared in accordance with Example 1
(102 g, 1.0 mol) was fed into a stirred slurry of sodium hydroxide
(80 g, 2.0 mol) in dimethyl sulphoxide (255 cm.sup.3) containing a
little water at 60.degree. C. On completion of the addition, the
reaction mixture was stirred for a further 10 hours at 60.degree.
C. to ensure complete reaction. On completion of the reaction the
product was removed by distillation at atmospheric pressure, bp
57.degree. C. to 62.degree. C. The yield was 59.4 g (87.3%) with a
purity of >98%.
* * * * *